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Reduced susceptibility to protease inhibitors (PI) in the absence of primary PI resistance-associated mutations
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Reported by Jules Levin
14th Intl HIV Drug Resistance Workshop
June 7-11, 2005
Quebec City, Quebec, Canada
N Parkin, C Chappey, E Lam, and C Petropoulos
Virologic, Inc, South San Francisco, CA, USA
BACKGROUND: The majority of clinical samples submitted for phenotypic and genotypic resistance testing that demonstrate reduced protease inhibitor (PI)
susceptibility also have one or more "primary" PI selected resistance-associated mutations (RAMs). However, occasionally samples are observed with unexplained PI resistance.
METHODS: Primary PI RAMs were defined as any change Vs wild-type at positions 23, 24, 30, 32, 46, 47, 48, 50, 54, 82, 84, 88, 90 with the following
exceptions: I54V and N88D (not reported to occur without other primary mutations) and V82I (known polymorphism in PI-naive patients).
PI susceptibility (fold-change [FC] in IC50), gag (positions 418-500)
and PR genotype were determined with the PhenoSense and GeneSeq assay, respectively (ViroLogic, Inc.). Fisher's exact test was used to determine
genotypic changes in gag or PR associated with reduced PI susceptibility; mixtures were counted as mutant, and variables with P<0.005 were considered
significant.
RESULTS: A small group of samples with no primary PI RAMs but at least one PI with FC>5 was identified (n=125; 0.5% of samples lacking PI RAMs); 28 had at least one PI with FC>10.
The median/maximum FC to amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, lopinavir, and atazanavir were 2.4/25, 3.1/15, 9.6/65, 5.2/75, 2.7/52, 2.4/28, and 3.6/41, respectively.
The number of samples with FC>5 to 1, 2, 3, or ≥4 PIs was 89 (mostly nelfinavir), 17 (mostly nelfinavir and ritonavir), 11, and 8, respectively.
Compared to 3956 samples with no PI RAMs and all PIs FC<5, PR mutations over-represented in samples with at least one PI FC>5 included: L10IV, I13V, L19V, K20IMT, A22V, M36IV, N37D, I54V, H69R, A71ITV, G73S, T74KS, V82I, N83D, N88D and I93L.
In gag, several changes including K418ER, A431V, I437V, L449IP, P453L,
and E482G were associated with PI FC>5.
CONCLUSIONS: Although rare, reduced susceptibility to PIs in excess of fivefold in the absence of primary mutations in PR can be observed in clinical samples. Accumulation of secondary mutations and/or polymorphisms in PR, as well as changes in the C-terminal region of gag, are potential contributors to reduced PI susceptibility and may modulate response to PI treatment.
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